Asthma is a multifactorial disease with environmental and genetic contributions. We demonstrated that the harm caused by early-life exposures to air pollution and tobacco varies among different racial/ethnic groups. Our recent genome-wide association studies have identified both shared and ethnic-specific genetic risk factors for asthma and asthma-related traits. Our findings imply that both genes and early-life environmental exposures are important contributors to asthma susceptibility in minority children. We hypothesize that racial/ethnic differences in asthma susceptibility are due to gene-environment interactions resulting from early-life exposure to air pollution and tobacco. We will use existing genome-wide SNP genotypes and two distinct but complimentary approaches-admixture mapping and novel genome-wide GxE interaction scanning methods-to investigate the relationship between genetics, early-life air pollution and tobacco smoke exposures, and asthma risk. Specific Aim 1: Ancestry by environment interaction analysis of asthma in minority children. We will use genome-wide estimates of local chromosomal ancestry (African, European, and Native American) to perform an admixture mapping by environment (AxE) scan in 6,536 Latino and African American children from across the U.S. We will fine map AxE interaction peaks by performing targeted GxE analyses of genotyped and imputed SNPs from CAAPA and the Thousand Genomes Project. Results will be replicated using similar outcomes and exposures in the Mexico City Childhood Asthma Study (MCCAS). Specific Aim 2: Genome-wide by environment (GxE) interaction analysis of asthma in ethnically diverse children with and without asthma. We will use a novel two-step analytical method to perform a genome-wide scan at 38.9 million SNPs for GxE interactions with air pollution and tobacco smoke exposure. Scans will be performed in our combined resource of 8,138 children, as well as within Latino, European, and African American subgroups. Results will be replicated using similar outcomes and exposures in MCCAS. EXPECTED OUTCOMES: We will identify genes and genetic loci whereby gene-environment interactions play an important role in asthma etiology, and thus retrieve part of the missing heritability of asthma. We will identify significant shared and ethnic specific gene-environment interactions, which will further our understanding of racial/ethnic differences in asthma susceptibility.